Cystathionine-γ-lyase(CSE),an enzyme associated with hydrogen sulfide(H2S)production,is an important endogenous regulator of inflammation.Jumonji domain-containing protein 3(JMJD3)is implicated in the immune response...Cystathionine-γ-lyase(CSE),an enzyme associated with hydrogen sulfide(H2S)production,is an important endogenous regulator of inflammation.Jumonji domain-containing protein 3(JMJD3)is implicated in the immune response and inflammation.Here,we investigated the potential contribution of JMJD3 to endogenous CSE-mediated inflammation in rheumatoid arthritis(RA).Upregulated CSE and JMJD3 were identified in synovial fibroblasts(SFs)from RA patients as well as in the joints of arthritic mice.Knocking down CSE augmented inflammation in IL-1β-induced SFs by increasing JMJD3 expression.In addition,CSE−/−mice with collagen-induced arthritis(CIA)developed severe joint inflammation and bone erosion.Conversely,overexpressing CSE inhibited JMJD3 expression by the transcription factor Sp-1 and was accompanied by reduced inflammation in IL-1β-treated SFs.Furthermore,JMJD3 silencing or the administration of the JMJD3 inhibitor GSK-J4 significantly decreased the inflammatory response in IL-1β-treated SFs,mainly by controlling the methylation status of H3K27me3 at the promoter of its target genes.GSK-J4 markedly attenuated the severity of arthritis in CIA mice.In conclusion,suppressing JMJD3 expression by the transcription factor Sp-1 is likely responsible for the ability of CSE to negatively modulate the inflammatory response and reduce the progression of RA.展开更多
AIM To study the effect of hydrogen sulfide (H2S) onsevere acute pancreatitis (SAP) in a rat model.METHODS: Sprague-Dawley (SD) rats were administeredan intraperitoneal injection of saline containing20% L-Arg ...AIM To study the effect of hydrogen sulfide (H2S) onsevere acute pancreatitis (SAP) in a rat model.METHODS: Sprague-Dawley (SD) rats were administeredan intraperitoneal injection of saline containing20% L-Arg (250 mg/100 g) hourly for over 2 h to induceSAP. The rats were treated with DL-propargylglycine(PAG, 50 mg/kg) or different dosages of NaHS (5 mg/kg, 10 mg/kg, 20 mg/kg or 100 mg/kg). PAG or NaHSwas administered 1 h before induction of pancreatitis.Rats were sacrificed 24 h after the last L-Arg injection.Blood and pancreas tissues were collected.RESULTS: The H2S and cystathionine-γ-lyase mRNAlevels in SAP rats were signi?cantly lower than thosein the control group, and treatment with PAG furtherreduced the H2S level. Nevertheless, H2S was significantlyincreased after NaHS administration compared with theSAP group, and the degree of upregulation was associatedwith the NaHS dosage. NaHS reduced the levels of plasmaamylase, interleukin-6 and myeloperoxidase in pancreatictissue. NaHS suppressed the degradation of IκBα and theactivity of nuclear factor-κB, as well as the phosphorylationof PI3K/AKT.CONCLUSION: H2S plays an anti-inflammatory role inSAP in vivo .展开更多
In the porcine model discussed in this review,the acute subdural hematoma was induced by subdural injection of autologous blood over the left parietal cortex,which led to a transient elevation of the intracerebral pre...In the porcine model discussed in this review,the acute subdural hematoma was induced by subdural injection of autologous blood over the left parietal cortex,which led to a transient elevation of the intracerebral pressure,measured by bilateral neuromonitoring.The hematoma-induced brain injury was associated with albumin extravasation,oxidative stress,reactive astrogliosis and microglial activation in the ipsilateral hemisphere.Further proteins and injury markers were validated to be used for immunohistochemistry of porcine brain tissue.The cerebral expression patterns of oxytocin,oxytocin receptor,cystathionine-γ-lyase and cystathionine-β-synthase were particularly interesting:these four proteins all co-localized at the base of the sulci,where pressure-induced brain injury elicits maximum stress.In this context,the pig is a very relevant translational model in contrast to the rodent brain.The structure of the porcine brain is very similar to the human:the presence of gyri and sulci(gyrencephalic brain),white matter to grey matter proportion and tentorium cerebelli.Thus,pressure-induced injury in the porcine brain,unlike in the rodent brain,is reflective of the human pathophysiology.展开更多
基金supported by grants from National Natural Science Foundation of China(No.8167342881330080)a key laboratory program of the Education Commission of Shanghai Municipality(No.ZDSYS14005).
文摘Cystathionine-γ-lyase(CSE),an enzyme associated with hydrogen sulfide(H2S)production,is an important endogenous regulator of inflammation.Jumonji domain-containing protein 3(JMJD3)is implicated in the immune response and inflammation.Here,we investigated the potential contribution of JMJD3 to endogenous CSE-mediated inflammation in rheumatoid arthritis(RA).Upregulated CSE and JMJD3 were identified in synovial fibroblasts(SFs)from RA patients as well as in the joints of arthritic mice.Knocking down CSE augmented inflammation in IL-1β-induced SFs by increasing JMJD3 expression.In addition,CSE−/−mice with collagen-induced arthritis(CIA)developed severe joint inflammation and bone erosion.Conversely,overexpressing CSE inhibited JMJD3 expression by the transcription factor Sp-1 and was accompanied by reduced inflammation in IL-1β-treated SFs.Furthermore,JMJD3 silencing or the administration of the JMJD3 inhibitor GSK-J4 significantly decreased the inflammatory response in IL-1β-treated SFs,mainly by controlling the methylation status of H3K27me3 at the promoter of its target genes.GSK-J4 markedly attenuated the severity of arthritis in CIA mice.In conclusion,suppressing JMJD3 expression by the transcription factor Sp-1 is likely responsible for the ability of CSE to negatively modulate the inflammatory response and reduce the progression of RA.
基金Supported by National Education Department“ChunHui Plan”Research Projects,No.Z2010021China Postdoctoral Science Foundation Project,No.2013M531079+2 种基金Heilongjiang Postdoctoral Funding Project,No.LBH-Z12246Heilongjiang Education Department Scientific Research Project,No.12521502excellent Innovative Talents Support Program Funding of Heilongjiang University of Chinese Medicine(Outstanding Young Academic Leaders),No.051217
文摘AIM To study the effect of hydrogen sulfide (H2S) onsevere acute pancreatitis (SAP) in a rat model.METHODS: Sprague-Dawley (SD) rats were administeredan intraperitoneal injection of saline containing20% L-Arg (250 mg/100 g) hourly for over 2 h to induceSAP. The rats were treated with DL-propargylglycine(PAG, 50 mg/kg) or different dosages of NaHS (5 mg/kg, 10 mg/kg, 20 mg/kg or 100 mg/kg). PAG or NaHSwas administered 1 h before induction of pancreatitis.Rats were sacrificed 24 h after the last L-Arg injection.Blood and pancreas tissues were collected.RESULTS: The H2S and cystathionine-γ-lyase mRNAlevels in SAP rats were signi?cantly lower than thosein the control group, and treatment with PAG furtherreduced the H2S level. Nevertheless, H2S was significantlyincreased after NaHS administration compared with theSAP group, and the degree of upregulation was associatedwith the NaHS dosage. NaHS reduced the levels of plasmaamylase, interleukin-6 and myeloperoxidase in pancreatictissue. NaHS suppressed the degradation of IκBα and theactivity of nuclear factor-κB, as well as the phosphorylationof PI3K/AKT.CONCLUSION: H2S plays an anti-inflammatory role inSAP in vivo .
基金This work was supported by a grant from the Deutsche Bundeswehr and the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)-Projektnummer 251293561-SFB 1149(to PR)a grant from the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)-Projektnummer 251293561-SFB 1149 and Ulm University-Baustein-Programm(to TM).
文摘In the porcine model discussed in this review,the acute subdural hematoma was induced by subdural injection of autologous blood over the left parietal cortex,which led to a transient elevation of the intracerebral pressure,measured by bilateral neuromonitoring.The hematoma-induced brain injury was associated with albumin extravasation,oxidative stress,reactive astrogliosis and microglial activation in the ipsilateral hemisphere.Further proteins and injury markers were validated to be used for immunohistochemistry of porcine brain tissue.The cerebral expression patterns of oxytocin,oxytocin receptor,cystathionine-γ-lyase and cystathionine-β-synthase were particularly interesting:these four proteins all co-localized at the base of the sulci,where pressure-induced brain injury elicits maximum stress.In this context,the pig is a very relevant translational model in contrast to the rodent brain.The structure of the porcine brain is very similar to the human:the presence of gyri and sulci(gyrencephalic brain),white matter to grey matter proportion and tentorium cerebelli.Thus,pressure-induced injury in the porcine brain,unlike in the rodent brain,is reflective of the human pathophysiology.